Project Summary Recent studies have shown that idiopathic Parkinson?s disease (PD), the second most common neurodegenerative disorder in the US, may originate in the gastrointestinal (GI) tract. From there it spreads via the vagus nerve to the brainstem and, subsequently, to the dopaminergic neurons of the substantia nigra pars compacta (SNpc). Indeed, GI symptoms such as gastroparesis and constipation are prodromal to the onset of PD. Recently, we discovered a nigro-vagal pathway that connects the SNpc to neurons of the dorsal motor nucleus of the vagus (DMV) and, upon SNpc stimulation, increases colonic motility. The nigro-vagal pathway is impaired in an experimental model of PD such that SNpc stimulation increases motility to a lesser extent. We have also generated a novel rodent model of environmental Parkinsonism, in which oral gavage of rats with subthreshold doses of the herbicide, paraquat (P), in combination with lectins (L), a sugar binding protein found commonly in the human diet, induces levodopa-responsive Parkinsonism. Such P+L treatment also induces generation of pathological ?-synuclein in the GI tract, as well as in the DMV and SNpc, with significant degeneration (~50%) of dopaminergic SNpc neurons. Our preliminary data indicate that P+L treatment also slowed gastro-cecal transit, attenuated the colonic response to excitation of the SNpc and altered the colonic response to brainstem dopamine administration. At the same time, DMV neurons become hyperactive to compensate for the decreased colonic motility. Based on our preliminary studies, that demonstrate that chemogenetic blockade of the nigro-vagal pathway prevents the development of PD, we propose the following novel hypothesis: ??-synucleinopathy- associated GI hypomotility induces maladaptive plasticity in the nigro-vagal pathway, favoring the progression of PD?. We further hypothesize that correction of this maladaptive neuroplasticity will forestall parkinsonism. To investigate this novel hypothesis, we will use a combination of in vivo chemogenetic and electrophysiological, anatomical and behavioral approaches in rodents to investigate the role of the neural pathways affected in parkinsonian-related GI dysfunctions and in the etiology of PD.